Phase II single-arm, multi-center, physician-initiated clinical trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) against diffuse intrinsic pontine gliomas.
Authors: Ryuta Saito, Masayuki Kanamori, Yohei Mineharu, Yoshiki Arakawa, Kentaro Chiba, Yasuo Aihara, Ichiyo Shibahara, Toshihiro Kumabe, Kenichiro Matsuda, Yukihiko Sonoda, Fumiaki Takahashi, Teiji Tominaga
Journal: Journal of Clinical Oncology (2022)

2071 Background: Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest central nervous system tumors of childhood, with a 1 year survival of 40%. Intracerebral convection-enhanced delivery (CED) is an approach for administering chemotherapy to patients with brain tumors. We present the results of a multi-institute physician-initiated phase II clinical trial of CED of nimustine hydrochloride (ACNU) against DIPGs. Methods: We did a phase 2, single-arm, multi-center, prospective, physician-initiated clinical trial. Eligible patients were aged 3–21 years and had initially diagnosed DIPG. A Karnofsky performance score of at least 50 at study entry; and had completed standard external beam radiation therapy at least 4 weeks but no more than 5 weeks before enrollment. Accrual of 20 patients were planned. The 1 year survival rate from study entry was set as the primary endpoint, and prespecified threshold of the lower limit level of the 95% confidence interval was set as 30%. CED of 7 mL ACNU at the concentration of 0.75 mg/mL was given intratumorally through the 1-2 cannulas implemented surgically. Use of oral or intravenous temozolomide chemotherapy was allowed simultaneously with CED of ACNU. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full dose of treatment), and all patients who was recruited in this trial were included in the safety analysis. This study is registered with Japan Registry of Clinical Trials (jRCT2021190003). Results: From April, 2018 to March, 2020, 21 children were enrolled in the trial, of whom 20 were evaluable for the primary endpoint. ACNU was not given for one patient because of the adverse event of intracerebral hemorrhage due to catheter insertion surgery. Other than this patient, all 20 patients got 1-2 catheters inserted and received CED of ACNU. For these patients, CED of 7 mL ACNU at the concentration of 0.75 mg/mL was given intratumorally through the 1-2 cannulas implemented surgically. Temozolomide chemotherapy was administered simultaneously in 15 patients. As a result, progression-free survival was 8.0 months and overall survival was 15 months. 1 year survival from recruitment was 55% and was 65% from initiation of standard radiation therapy. Conclusions: As the lower limit level of the 95% confidence interval of the 1 year survival rate from recruitment to the study, which was the primary end-point of the study, exceeded prespecified threshold of 30%, CED of ACNU in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be an effective therapeutic strategy. This therapeutic strategy warrants further development for children with DIPG. Clinical trial information: jRCT2021190003.